We have been studying clathrin-independent forms of endocytosis (CIE) and have identified a number of endogenous PM proteins that enter cells through this mechanism. We have begun to study these proteins in detail in an attempt to understand how they travel in cells and whether they specifically interact with cellular machinery. We have identified signals in the cytoplasmic tails of CD44, CD98 and CD147 that are responsible for their altered trafficking and are looking for cellular machinery that is responsible for recognition and sorting of these signals. Some of the cargo interacting proteins may associate with the cargo at the cell surface. Understanding how these proteins move into and out of cells is important because these proteins are involved in interaction with the extracellular matrix (CD44), are involved in nutrient transport (CD98) and interact with integrins and matrix metalloproteinases (CD147). One interesting observation that we made concerns the coordinate regulation of clathrin-mediated and clathrin-independent endocytosis (CME and CIE, respectively). We found that when CME is blocked, by transient transfection of dominant negative clathrin machinery or siRNA depletion of clathrin machinery, CIE continues but the itinerary of CIE cargo proteins is altered. Cargo proteins that typically do not go on to degradation (CD98 and CD147) now traffic to late endosomes and are degraded (Dutta and Donaldson, 2015). Interestingly, we found that it is Rab35 that acts to signal that CME is functioning by recruiting an Arf6 GAP (ACAP) to inactivate Arf6. Expression of Rab35 dominate negative or siRNA depletion of Rab35 recreates this altered trafficking observed when CME is blocked.